We have documented age-related and degeneration-related changes in the metabolism of collagens, proteoglycans, and matrix-degrading enzymes in the human intervertebral disc. Our studies (i) confirmed the pivotal roles that cytokines and growth factors play in intervertebral disc degeneration and repair, (ii) demonstrated that certain growth factors inhibit the autocrine production of cytokines and that cytokine inhibitors can change basal levels of synthesis of matrix molecules and metalloproteinases, and (iii) found that biglycan was expressed in greater amounts than other small proteoglycans during late stages of disc degeneration and in the discs of old donors and plays an important regulatory role in matrix homeostasis. Our data suggest that an intricate balance of growth factors, cytokines and regulatory molecules is important for the maintenance of tissue homeostasis. Over the next five years, we propose to investigate the mechanisms of action and the interplay between growth factors, cytokines and various regulatory molecules in order to determine their respective roles in tissue homeostasis and their potential use in promoting tissue repair. Hypothesis 1: The effects of growth factors on the intervertebral disc are regulated by the production of cytokines by intervertebral disc cells and by the presence of inhibitory factors; growth factors have a negative feed back on the production of these cytokines. Hypothesis 2: The regulatory mechanisms of matrix homeostasis by cytokines and growth factors vary at different stages of disc degeneration because of changes in the cellular microenvironment in situ within the disc. The response to cytokines and growth factors and the production and activation of matrix-degrading enzymes will be different at advanced stages of disc degeneration. Hypothesis 3: The inhibition of cytokine action by cytokine blockers and the inhibition of cytokine production by growth factors can delay or reverse the degenerative status of intervertebral disc cells in the cellular microenvironment that can be observed in the early and middle stages of disc degeneration. Low back pain is responsible for enormous human suffering, high health care costs and significant socioeconomic losses. Although the etiology of back pain is often unknown, the intervertebral disc is a significant source of back problems. The results from this study will advance the field of biological treatment and tissue engineering for intervertebral disc degeneration.